Abstract Type 2 diabetes mellitus (T2DM) is a strong risk factor for heart failure (HF), and is increasingly prevalent in the US. Epidemiologic evidence suggests increased blood pressure, higher hemoglobin A1c and increased obesity are risk factors for HF among diabetics. Currently there is not a simple, clinically useful way to risk- stratify diabetic patients with respect to future HF risk. This has led to interest in utilizing a blood test measuring NT-proBNP as part of risk stratification in persons with diabetes. Cardiac myocytes release proBNP, which is cleaved into the active BNP and inactive NT-proBNP, which is more stable in blood. The two are highly correlated and are utilized in diagnosing acute HF. NT-proBNP has been shown to be predictive of future HF, other cardiovascular events, and mortality. However small studies have suggested that increased body mass index (BMI) and A1c is associated with lower, rather than higher BNP/NT-pro BNP levels, in diabetics. These associations are counterintuitive, given the suggested relationship between HbA1c or BMI and HF. Furthermore, there is little data regarding change in NT-proBNP over time in diabetics without overt heart failure. Understanding the true relationship between risk factors for HF and NT-proBNP in T2DM is required before it could be useful to target HF prevention. Thus we propose an ancillary study to Look AHEAD (Action for Health in Diabetes) a multicenter, randomized trial which enrolled 5,145 overweight and obese adults with T2DM during 2001-04, to determine the long-term effects of an intensive lifestyle intervention designed to achieve and maintain weight loss by decreased caloric intake and increased physical activity versus a control condition, diabetes support and education (DSE), on the combined incidence of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. At one year, the effect of the intervention on weight was -8.3%, compared to -0.4% in the DSE group. This study proposes to test for NT- proBNP in 1500 Look AHEAD participants free of cardiovascular disease (750 in each arm) in stored frozen blood samples from baseline and one year. This study will lead to a better understanding of the correlates of NT-proBNP in overweight diabetic adults, and determine if a lifestyle intervention reduces NT-proBNP. The research proposed may lead to efforts to better identify diabetic adults at high risk for heart failure, and target prevention efforts. This is important, as heart failure is a common, deadly, and expensive illness in the U.S.PUBLIC HEALTH RELEVANCE It is known that blood levels of NT-proBNP can predict who will develop heart disease, including heart failure, but among diabetic persons, to determinants of NT-proBNP are not clear. This project aims to better understand NT-proBNP levels, and to test whether a weight loss intervention reduces the amount of NT- proBNP in the blood of diabetics. This may help better prevent heart failure in diabetics, which is important because heart failure is a common and deadly complication of diabetes.